CHRONIC COCAINE ADMINISTRATION INDUCES ENHANCED NORCOCAINE FORMATION IN THE RAT

Abstract

S364 INTRODUCTION: Cocaine (6%) is metabolized to norcocaine (nor) by liver cytochrome-P-450IIB1. Nor is a potent neurotoxin and hepatotoxin, as well as a modulator of hemodynamic responses and cardiac hormone release. In vitro, microsomal studies suggest that cocaine pretreatment may enhance norcocaine formation. We wished to determine, using a newly developed, highly sensitive, and accurate, LC/MS technique, whether chronic cocaine administration altered the metabolism and thus plasma metabolite concentrations of cocaine in vivo. METHODS: Eight (8) male Sprague-Dawley rats ([similar]400g) were fitted with internal jugular vein catheters connected to an Alzet Infusion pump (2002) (Alza Corporation,CA) primed, 12 hours earlier to administer continuously, over a 13 day period, 90mg/kg cocaine hydrochloride in saline (Group COC n = 5) or just saline (Group SAL, n = 3). On day 14, the osmotic pump was removed, and the femoral artery and vein catheterized and tunneled to the nape and exteriorized under a plastic hood. The following day (day 15) conscious rats were weighed and cocaine HCL 2.5mg/kg was administered iv, after which repetitive arterial blood samples were taken for cocaine, nor, benzoylecgonine (be) and ecgonine methylester (eme) analysis by LC/MS with a limit of detection of 2,2,2 and 5 ng/ml respectively. Plasma sample concentrations for each individual animal were fitted to a two compartment open model using WinNonlin (SCI Software, NC). The derived kinetic data and the area under the curves (AUC) of the metabolites were grouped and compared using the two tailed t-test. P < 0.05 was held to be significant. RESULTS: The mean concentration of cocaine and nor, from chronic cocaine infusion was 32 ng/ml and 0 ng/ml (n=5) respectively at time of femoral arterial catheterization (Day 14), on the day prior to cocaine bolus dose administration. The plasma decay of cocaine after a bolus dose as well as metabolite formation is demonstrated in Figure 1. (Table 1)Figure 1Table 1DISCUSSION: These preliminary data indicate that while the pharmacokinetic disposition of cocaine is unaffected by chronic cocaine administration norcocaine formation is enhanced. This suggests a mechanism for the enhanced toxicity from chronic cocaine ingestion.